Liječenje infertiliteta uzrokovanog HLA-D statusom roditelja

Duić, Željko (2003) Liječenje infertiliteta uzrokovanog HLA-D statusom roditelja. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Habitual abortion or recurrent spontaneous abortion is defined as a sequence of three or more pregnancies ending as miscarriage; if such a series has been preceded by a normal, successful pregnancy, it is called “secondary habitual abortion“, if not, the term “primary habitual abortion“ is used. In approximately 40% of the habitual abortions no causative factor can be determined, in this group of patients an immunological rejection reaction is suspected, although at present no distinctive pathognomonic clinical or laboratory criteria are available to characterize this subgroup of habitual abortion. Forty primary aborters enrolled in study to receive infusion humane intravenous immunoglobuline (IVIG) or didrogesteron tablet à 10 mg starting as soon as pregnancy test was positive. The aim of this study was to present the results of the treatment and eventually evidence for therapeutic effect IVIG/didrogesteron in women who had suffered at least three recurrent miscarriage. IVIG was first produced at the Institute of Immunology in Zagreb, Croatia. In this study, partners with histocompatbility in HLA-D loci were included. Tissue typing was carried out at the Tissue Typing Center, University Hospital Center Rebro, Zagreb. Before treatment at our hospital all the patients with the possibility of the chromosomal aberrations, genopaties, anatomic, microbiological, endocrinological, environmental factors or autoimmunization as a cause of abortion were excluded. Treatment (IVIG/didrogesteron, bed rest) started after confirmation of pregnancy on the fifth week of pregnancy. First infusion contained 30 grams of IVIG. Further five/six doses of 20 grams were infused every third week. Total dose of IVIG was 130/150 grams per case. All pregnancies, except one, were treated at our hospital, but five women were gave birth out of our hospital. Success was defined as pregnancy beyond gestational week 24 and/or delivery. In IVIG group: Twenty women parcipitated in study. Their average age was 31,8 years (range 24-40). Seventeen out of twenty pregnant women delivered 19 babies (one triplets). One pre-term at 28 weeks born baby died 3 hour after birth. Three abortions occurred after the first or second infusion. Due to obstetrics reasons ten deliveries were terminated by caesarean section (58,82%). Three pregnancies were (17,64%) terminated before 37 gestation weeks. Two babies were born small for gestational age. Three patients developed H-gestosis. Three women had pre-term labor pain and were treated with infusion of ritodrin. Due to incompetence of cervix in 5 cases in second trimester of pregnancy cervical cerclage were done (29,41%) In control group (bed rest, didrogesteron tablet à 10 mg until 12th weeks) the average age of women receiving didrogesteron was 27,9 years (range 22-36). Out of twenty, 18 pregnant women gave birth to 19 babies (one twins). Success rate was 90% (18/20). Twins were born at 26 weeks pre-term, and died several hours later. Three women had pre-term delivery (16,66%), in one of them caesarean section was done in 34th weeks of gestation due to worsening universal fetal hydrops. Baby was died 12 hours after delivery due to hydrops unknown etiology. Due to pre-term uterine contractions we treated five pregnant women with infusion of ritodrin. Due to incompetence of cervix in 6 cases in second trimester of pregnancy cervical cerclage was done (33,33%). Due to obstetrics reasons 5 deliveries were terminated by caesarean section (27,77%). The average weight of the newborns was 2863,2g (range 400g-3650g) in the IVIG group and 2925,8g (range 480g-4350g) in didrogesteron group. The average gestational ages were 38,11 weeks (range 29-41) in the IVIG group and 36,16 weeks (range 26-41 weeks) in control groups. No congenital malformations were observed in the newborns. In all, with no significant differences in the pregnancy course or perinatal outcome between those two-treatment group (IVIG/didrogesteron) were found. May be due to imunomodulatory effects of progesterone or emotional care associated with administration of placebo can indirectly facilitating the progression of pregnancy. Serum levels of TNF and IL2 were not significantly associated with pregnancy outcome. We did not found statistical significant differentiation in serum concentration of TNF and IL2 between IVIG group and control group. We found statistical significant elevation of serum concentration TNF in first trimester pregnancy of women with history of at least 3 consecutive spontaneous abortions, in addition first trimester normal pregnancy Only six patients in IVIG group had side effects at the time of the first infusion and they were: headache, nausea, chills, and elevated body temperature under 38 C, hot flushing, and chill. Side effects disappeared after reducing the speed of infusion.

Abstract in Croatian

Habitualni ili učestali spontani pobačaji definiraju se kao tri ili više uzastopne trudnoće završene pobačajem. Imenuju se sekundarnim habitualnim pobačajima, ako im prethodi bar jedan porod živog djeteta, a primarnim habitualnim pobačajima kada su bez uspješno završene trudnoće. U približno 40% parova koji habitualno pobacuju nije nađen uzrok pobacivanja, te je vjerojatno određen broj tih pobačaja imunološki uzrokovan, iako nema patognomoničnih kliničkih ili laboratorijskih kriterija kojima bi se dokazali aloimunološki uzrokovani pobačaji. U ispitivanje smo uključili 40 parova s iskustvom od tri i više uzastopnih spontanih pobačaja, prvog tromjesečja, kod kojih smo isključili anatomski, endokrinološki, metabolički, upalni, autoimunosni i druge uzroke pobacivanja te pretpostavili vjerojatni aloimunološki uzrok pobacivanja (podudarnost u HLA-D antigenima). Uz pismeni pristanak parova te uz odobrenje Etičkog povjerenstva KB»Merkur» i Medicinskog fakulteta uključili smo ih u ispitivanje. Nakon utvrđivanja trudnoće ultrazvukom ili s pozitivnim β-lancom humanog horionskog gonadotropina, zadovoljavanja kriterija za izbor parova, proveli smo prospektivno kontrolirano randomizirano (tablica slučajnih brojeva) kliničko ispitivanje: 20 trudnica liječili smo IVIG-om, prva infuzija od 30 grama IVIG-a. Sljedećih pet/šest infuzija IVIG po 20 grama trudnice su dobile u razmacima od po tri tjedna sve do 22-24. tjedna trudnoće. Ukupna doza IVIG bila je 130/150 grama. Drugih 20 trudnica smo liječili uobičajnom intenzivnom skrbi- mirovanje, didrogesteron. Kod svih ispitanica postojala je podudarnost u HLA–D lokusima među partnerima. Eritrocitni i leukocitni antigeni ustanovljeni su u Centru za tipizaciju tkiva KBC Rebro u Zagrebu. Sve indikacije postavljene su u KB»Merkur». Od 40 ispitanica uključenih u studiju tri su rodile u Splitu, jedna u Karlovcu, jedna u Bjelovaru. Kao kriterije uspjeha terapije uzeli smo trudnoće i porode iznad 24. tjedna gestacije. Kariotipovi svih pobačenih zametaka bili su uredni. Ukupan broj pobačaja u IVIG skupini je 73, ili prosječno 3,63 po trudnici, dok je 60 u kontrolnoj skupini ili prosječno 3,0 po trudnici. U skupini IVIG ispitanice su bile u dobi od 24 do 40 godina, a prosječna dob iznosila je 31,8 godina. Od 20 trudnica 17 je rodilo što je 85% (17/20). Tri trudnoće okončane su pobačajem u prvom tromjesečju, što je 15% (3/20). Broj živorođene djece iz 17 poroda je 19 (jedni trojci). Učestalost prijevremenog poroda je 17,64% (3/17porođenih). Carskim rezom zbog opstetričkih indikacija završeno je 10 poroda što je 58,82% (10/17). H-gestozu imale su 3 trudnice što je 17,64% (3/17 poroda). U 3 trudnice zbog prijetećeg prijevremenog poroda započeto je liječenje ritodrinom intravenski i per os (3/17). Serklaža je učinjena u 5 trudnica što je 29,41% (5/17) na broj poroda ili 25% ako se uzmu sve ispitanice (5/20). Manja za gestacijsku dob bila su 2 novorođenčeta. Srednja gestacijska dob pri porodu je 38,11 tjedana (od 29 do 41 tjedan). Srednja tjelesna težina novorođenčeta je 2863,2g (u rasponu od 400g do 3650g). U kontrolnoj skupini ispitanice su bile u dobi 22 od 36 godina, prosječna dob bila je 29,7 godina. Od 20 trudnica 18 je rodilo, a 2 su pobacile. Stopa uspjeha je 90% (18/20). Broj živorođene djece iz 18 poroda je 19. Prije navršenih 37. tjedna završile su 3 trudnoće ili 16,66% (3/18). Ritodrinom intravenski ili per os zbog prijetećeg pobačaja liječeno je 5 trudnica. Serklaža je učinjena u 6 ispitanica što je 33,33% (6/18 poroda) ili 30% ako su računaju sve ispitanice (6/20). Carskim rezom zbog opstetričkih indikacija dovršeno je 5 poroda ili 27,77% (5/18). Srednja gestacijska dob pri porodu je 36,16 tjedana (od 26 do 41 tjedan). Srednja tjelesna težina novorođenčeta je 2925,8g (od 480 do 4350g). Srednja vrijednost koncentracije TNFα i IL-2 u serumu IVIG/kontrole kroz sva tri promatrana perioda nisu pokazale statistički značajnu razliku. Srednja vrijednost TNFα zdravih trudnica u 1. periodu je 23,2 pg/ml, dok je u habitualnih pobacilja 61,8 pg/ml (IVIG i kontrolnoj skupini). Statistički je značajno viša koncentracija TNFα u serumu habitalnih pobacilja u odnosu na zdrave trudnice. Ne postoji statistički značajna razlika u koncentraciji IL-2 u serumu zdravih trudnica u odnosu na habitualne pobacilje. Srednja vrijednost koncentraije IL2 u zdravih trudnica u 1. periodu je 73,66 pg/ml, a u habitualnih pobacilja 85,3 pg/ml (IVIG i kontrolna skupina). Blage nuspojave pojavile su se u 6 trudnica koje su primale IVIG uvijek pri rimanju prve doze. To su glavobolja, mučnina, tresavica, osjećaj vrućine temperatura do 38 C i crvenilo kože. Smanjivanjem brzine infuzije simptomi su se povlačili.

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